The trials discussed in the present review generally included ambulatory patients who were stable on the accepted contemporary therapy for heart failure (ACE inhibitors, digitalis, and diuretics).33,34,36,39 Patients with heart rates below 60 to 68 beats per minute and systolic blood pressures below 90 to 100 mm Hg were excluded from the studies. With the exception of the US Carvedilol Heart Failure Trials Program, which had an active run-in period, the trials were initiated after a period of stabilization on standard therapy followed by a placebo run-in period. Patients completing the run-in periods were randomized in their respective trials and were gradually up-titrated over a 6- to 8-week period to a total maximum target dose (10 mg of bisoprolol daily, 50 mg [<75 kg] or 100 mg [>75 kg] of bucindolol hydrochloride twice daily, or 200 mg of metoprolol CR/XL daily; maximum target doses of carvedilol varied among the 4 protocols, ranging from 6.25 mg twice daily to 50 mg twice daily).33,34,36,39 These drugs were well tolerated; most patients were titrated to maximum or near maximum doses. For example, at completion of MERIT-HF, 64% of patients had achieved the maximum target dose of 200 mg of metoprolol CR/XL per day, 87% had achieved a dose of 100 mg or more of metoprolol CR/XL per day,41 and 43% of patients in CIBIS-II had achieved the target dose of 10 mg of bisoprolol per day.42 The dosing schedules used in these 3 trials are given in Table 3. There were no differences in discontinuations between the active and placebo arms of these trials, although assessment of both adverse events and discontinuations in the US Carvedilol Heart Failure Trials Program is confounded because of the open-label run-in phase. Because of this, patients who died during the run-in phase or did not tolerate carvedilol were excluded. In MERIT-HF, compared with the placebo group, withdrawal of the study drug from all causes was 10% lower (Figure 8) and withdrawal due to worsening heart failure was 25% lower in the metoprolol CR/XL group, although this finding did not reach statistical significance.35 Contrary to common belief, these trials demonstrate that β-blockers are well tolerated in patients with heart failure; with initiation at low doses and careful titration, most patients can achieve a maximum therapeutic dose. In the setting of worsening failure during β-blocker therapy, the β-blocker dose should not be up-titrated further and, if necessary, can be decreased gradually.